Skip to main content
SpringerLink
Log in

Graves’ ophthalmopathy: State of the art and perspectives

  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Graves’ ophthalmopathy (GO) is an autoimmune orbital disorder most commonly associated with Graves’ disease. Recent studies have underscored the role that orbital cells, particularly fibroblasts and adipocytes, play in causing the increase in orbital content responsible for clinical manifestations of the disease. GO seems to be related to autoimmune reactions triggered by autoreactive T lymphocytes of thyroid origin, which recognize antigen(s) shared by thyroid and orbit. The nature of the antigen (or antigens) involved is not fully understood, but TSH receptor is likely to be involved. Cytokines secreted by T lymphocytes, macrophages and fibroblasts play an essential role in perpetuating the disease. Animal models of GO have been developed, but results have not clarified GO pathogenesis yet. Progress in the management of the ophthalmopathy has been very limited, and glucocorticoids, orbital radiotherapy and orbital decompression remain the mainstays in GO treatment. Novel treatments, such as somatostatin analogues, antioxidants, cytokine antagonists are currently under investigation, as well as the effects of total thyroid ablation. Cessation of smoking currently represents the only form of GO (secondary and tertiary) prevention.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bartalena L, Pinchera A, Marcocci C. Management of Graves’ ophthalmopathy: reality and perspectives. Endocr Rev 2000, 21: 168–99.

    PubMed  CAS  Google Scholar 

  2. Wiersinga WM, Bartalena L. Epidemiology and prevention of Graves’ ophthalmopathy. Thyroid 2002, 12: 855–60.

    Article  PubMed  Google Scholar 

  3. Bartalena L, Marcocci C, Pinchera A. Graves’ ophthalmopathy: a preventable disease? Eur J Endocrinol 2002, 146: 457–61.

    Article  PubMed  CAS  Google Scholar 

  4. Bartalena L, Bogazzi F, Tanda ML, Manetti L, Dell’Unto E, Martino E. Cigarette smoking and the thyroid. Eur J Endocrinol 1995, 133: 507–12.

    Article  PubMed  CAS  Google Scholar 

  5. Bartalena L. Smoking and Graves’ disease. J Endocrinol Invest 2002, 25: 402.

    Article  PubMed  Google Scholar 

  6. Hegedus L, Brix TH, Vestergaard P. Relation between cigarette smoking and Graves’ ophthalmopathy. J Endocrinol Invest 2004, 27: 265–71.

    Article  Google Scholar 

  7. Gerding MN, Terwee CB, Dekker FW, Koornneef L, Prummel MF, Wiersinga WM. Quality of life in patients with Graves’ ophthalmopathy is markedly decreased: measurement by the Medical Outcomes Study Instrument. Thyroid 1997, 7: 885–9.

    Article  PubMed  CAS  Google Scholar 

  8. Bartley GB, Fatourechi V, Kardmas EF, et al. Long-term follow-up of Graves’ ophthalmopathy in an incidence cohort. Ophthalmology 1996, 103: 958–62.

    Article  PubMed  CAS  Google Scholar 

  9. Ludgate M, Baker G. Inducing Graves’ ophthalmopathy. J Endocrinol Invest 2004, 27: 211–5.

    Article  PubMed  CAS  Google Scholar 

  10. Costagliola S, Many MC, Stalmans Falys M, et al. Transfer of thyroiditis, with syngeneic spleen-cells sensitized with the human thyrotropin receptor, to naive BALB/c and NOD mice. Endocrinology 1996, 137: 4637–43.

    PubMed  CAS  Google Scholar 

  11. Many MC, Costagliola S, Detrait M, Denef JF, Vassart G, Ludgate M. Development of an animal model of autoimmune thyroid eye disease. J Immunol 1999, 162: 4966–74.

    PubMed  CAS  Google Scholar 

  12. Costagliola S, Many MC, Denef JF, Pohlenz J, Refetoff S, Vassart G. Genetic immunisation of outbred mice with thyrotropin receptor cDNA provides a model of Graves’ disease. J Clin Invest 2000, 105: 803–11.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  13. Coles AJ, Wing N, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999, 354: 1691–5.

    Article  PubMed  CAS  Google Scholar 

  14. Bahn RS. TSH receptor expression in orbital tissue and its role in the pathogenesis of Graves’ ophthalmopathy. J Endocrinol Invest 2004, 27: 216–20.

    Article  PubMed  CAS  Google Scholar 

  15. Davies TF. The thyrotropin receptors spread themselves around. J Clin Endocrinol Metab 1994, 79: 1232–3.

    PubMed  CAS  Google Scholar 

  16. Marinò M, Chiovato L, Lisi S, Altea MA, Marcocci C, Pinchera A. Role of thyroglobulin in the pathogenesis of Graves’ ophthalmopathy: the hypothesis of Kriss revisited. J Endocrinol Invest 2004, 27: 230–6.

    Article  PubMed  Google Scholar 

  17. McDougall IR, Kriss JP. New thoughts about the case and treatment of the severe ocular manifestations of Graves’ disease. Scott Med J. 1974, 19: 165–9.

    PubMed  CAS  Google Scholar 

  18. Marinò M, Lisi S, Pinchera A, et al. Identification of thyroglobulin in orbital tissues of patients with thyroid-associated ophthalmopathy. Thyroid 2001, 11: 177–85.

    Article  PubMed  Google Scholar 

  19. Lisi S, Marinò M, Pinchera A, et al. Thyroglobulin in orbital tissues from patients with thyroid associated ophthalmopathy: predominant localization in fibroadipose tissue. Thyroid 2002, 12: 351–60.

    Article  PubMed  CAS  Google Scholar 

  20. Mariotti S, Pisani S, Russova A, Pinchera A. A new solid-phase immunoradiometric assay for anti-thyroglobulin autoantibody. J Endocrinol Invest 1982, 5: 27–33.

    Article  Google Scholar 

  21. Rose NR. Differing responses of inbred rat strains in experimental autoimmune thyroiditis. Cell Immunol 1975, 18: 360–4.

    Article  PubMed  CAS  Google Scholar 

  22. Mikozami T, Salvi M, Wall JR. Eye muscle antibodies in Graves’ ophthalmopathy: pathogenic or secondary epiphenomenon? J Endocrinol Invest 2004, 27: 221–9.

    Google Scholar 

  23. Hiromatsu Y, Fukazawa H, Guinard F, Salvi M, How J, Wall JR. A thyroid cytotoxic antibody that cross-reacts with an eye muscle cell surface antigen may be the cause of thyroidassociated ophthalmopathy. J Clin Endocrinol Metab 1988, 67: 565–70.

    Article  PubMed  CAS  Google Scholar 

  24. Kubota S, Gunji K, Stolarski C, Kennerdell JS, Wall JR. Role of eye muscle antibody measurement in diagnosis of thyroid-associated ophthalmopathy: a laboratory update. Endocr Prac 1998, 4: 127–31.

    Article  CAS  Google Scholar 

  25. Ajjan RA, Weetman AP. New understanding of the role of cytokines in the pathogenesis of Graves’ ophthalmopathy. J Endocrinol Invest 2004, 27: 237–45.

    Article  PubMed  CAS  Google Scholar 

  26. Heufelder AE, Bahn R. Detection and localization of cytokine immunoreactivity in retro-ocular connective tissue in Graves’ ophthalmopathy. Eur J Clin Invest 1993, 23: 10–7.

    Article  PubMed  CAS  Google Scholar 

  27. McLachlan SM, Prummel MF, Rapoport B. Cell-mediated or humoral immunity in Graves’ ophthalmopathy? Profiles of T-cell cytokines amplifies by polymerase chain reaction from orbital tissue. J Clin Endocrinol Metab 1994, 78: 1070–4.

    PubMed  CAS  Google Scholar 

  28. Hiromatsu Y, Yang D, Bednarczuk T, Mayake I, No K, Inoue Y. Cytokine profile in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 2000, 85: 1194–9.

    PubMed  CAS  Google Scholar 

  29. Heufelder AE, Smith J, Gorman CA, Bahn RS. Increased induction of HLA-DR by interferon-γ in cultured retroocular fibroblasts from patients with Graves’ ophthalmopathy and pretibial myxedema. J Clin Endocrinol Metab 1991, 73: 307–13.

    Article  PubMed  CAS  Google Scholar 

  30. Heufelder AE. Pathogenesis of Graves’ ophthalmopathy: recent controversies and progress. Eur J Endocrinol 1995, 132: 532–41.

    Article  PubMed  CAS  Google Scholar 

  31. Heufelder AE, Bahn RS. Modulation of intercellular adhesion molecule-1 (ICAM-1) by cytokines and Graves’ Igs in cultured Graves’ retroocular fibroblasts. Eur J Clin Invest 1992, 23: 10–7.

    Article  Google Scholar 

  32. Heufelder AE, Bahn RS. Modulation of Graves’ orbital fibroblast proliferation by cytokines and glucocorticoid receptor agonists. Ophthalmol Vis Sci 1994, 35: 120–7.

    CAS  Google Scholar 

  33. Ajjan RA, Weetman AP. Cytokines in Graves’ disease. In: Rapoport B, McLachlan S eds. Graves’ disease: pathogenesis and treatment. Norwell: Kluiwer Academic Publ. 2000, 79–93.

    Chapter  Google Scholar 

  34. Cao HJ, Smith TJ. Leukoregulin upregulation of prostaglandin endoperoxide H synthase-2 expression in human orbital fibroblasts. Am J Physiol 1999, 277: 1075–85.

    Google Scholar 

  35. Sorisky A, Pardasani D, Gagnon A, Smith TJ. Evidence of adipocyte differentiation in human orbital fibroblasts in primary culture. J Clin Endocrinol Metab 1996, 81: 3428–31.

    PubMed  CAS  Google Scholar 

  36. Smith TJ. Novel aspects of orbital fibroblast pathology. J Endocrinol Invest 2004, 27: 246–53.

    Article  PubMed  CAS  Google Scholar 

  37. Weightman DR, Perros P, Sherif IH, Kendall-Taylor P. Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity 1993, 16: 251–7.

    Article  PubMed  CAS  Google Scholar 

  38. Valyasevi RW, Harteneck DA, Dutton CM, Bahn RS. Stimulation of adipogenesis, peroxisome proliferator-activated receptor- γ (PPAR- γ), and thyrotropin receptor by PPAR- γ agonist in human orbital preadipocyte fibroblasts. J Clin Endocrinol Metab 2002, 87: 2352–8.

    PubMed  CAS  Google Scholar 

  39. Starkey K, Heufelder AE, Baker G, et al. PPAR γ in thyroid eye disease: contraindication to thiazolidenedione use? J Clin Endocrinol Metab 2003, 88: 55–9.

    Article  PubMed  CAS  Google Scholar 

  40. Bartalena L, Tanda ML, Piantanida E, Lai A. Oxidative stress and Graves’ ophthalmopathy: in vitro studies and therapeutic implications. Biofactors 2003, 19: 155–63.

    Article  PubMed  CAS  Google Scholar 

  41. Burch HB, Lahiri S, Bahn RS, Barnes S. Superoxide radical production stimulates retroocular fibroblast proliferation in Graves’ ophthalmopathy. Exp Eye Res 1997, 65: 311–6.

    Article  PubMed  CAS  Google Scholar 

  42. Hiromatsu Y, Yang D, Miyake I, et al. Nicotinamide decreases cytokine-induced activation of orbital fibroblasts from patients with thyroid-associated ophthalmopathy. J Clin Endocrinol Metab 1998, 83: 121–4.

    Article  PubMed  CAS  Google Scholar 

  43. Lu R, Wang P, Wartofsky L, et al. Oxygen free radicals in interleukin-1β-induced glycosaminoglycan production by retro-ocular fibroblasts from normal subjects and Graves’ ophthalmopathy patients. Thyroid 1999, 9: 297–303.

    Article  PubMed  CAS  Google Scholar 

  44. Heufelder AE, Wenzel BE, Bahn RS. Methimazole and propylthiouracil inhibit the oxygen free radical-induced expression of a 72 kilodalton heat shock protein in Graves’ retroocular fibroblasts. J Clin Endocrinol Metab 1992, 73: 307–13.

    Article  Google Scholar 

  45. Hiromatsu Y, Sato M, Yamada K, Nonaka K. Nicotinamide and 3-amidobenzamide inhibit recombinant interferon- γ-induced HLA-DR antigen expression, but not HLA-A, B, C antigen expression, on cultured human thyroid cells. Clin Endocrinol (Oxf) 1992, 36: 91–5.

    Article  CAS  Google Scholar 

  46. Hiromatsu Y, Sato M, Tanaka K, Ishisaka N, Kamachi J, Nonaka K. Inhibitory effects of nicotinamide on intercellular adhesion molecule-1 expression on cultured human thyroid cells. Immunology 1993, 80: 330–2.

    PubMed Central  PubMed  CAS  Google Scholar 

  47. Bartalena L, Marcocci C, Pinchera A. Cytokine antagonists: new ideas for the management of Graves’ ophthalmopathy. J Clin Endocrinol Metab 1996, 81: 446–8.

    PubMed  CAS  Google Scholar 

  48. Tan GH, Dutton CM, Bahn RS. Interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptor inhibit IL-1-induced glycosaminoglycan production in cultured human orbital fibroblasts from patients with Graves’ ophthalmopathy. J Clin Endocrinol Metab 1996, 81: 449–52.

    PubMed  CAS  Google Scholar 

  49. Marcocci C, Marinò M, Rocchi R, Menconi F, Morabito E, Pinchera A. Novel aspects of immunosuppressive and radiotherapy management of Graves’ ophthalmopathy. J Endocrinol Invest 2004, 27: 272–80.

    Article  PubMed  CAS  Google Scholar 

  50. Marcocci C, Bartalena L, Tanda ML, et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves’ ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab 2001, 86: 3562–7.

    PubMed  CAS  Google Scholar 

  51. Bartalena L, Marcocci C, Tanda ML, Pinchera A. Management of thyroid eye disease. Eur J Nucl Med 2002, 29 (Suppl. 2): S458–65.

    Article  Google Scholar 

  52. Bartalena L, Marcocci C, Gorman CA, Wiersinga WM, Pinchera A. Orbital radiotherapy for Graves’ ophthalmopathy: useful or useless? Safe or dangerous? J Endocrinol Invest 2003, 26: 5–18.

    Article  PubMed  CAS  Google Scholar 

  53. Krassas GE. Somatostatin analogues: a new tool for management of Graves’ ophthalmopathy. J Endocrinol Invest 2004, 27: 281–7.

    Article  PubMed  CAS  Google Scholar 

  54. Krassas GE, Heufelder AE. Immunosuppressive therapy in patients with thyroid eye disease: an overview of current concepts. Eur J Endocrinol 2001, 144: 311–8.

    Article  PubMed  CAS  Google Scholar 

  55. Bartalena L, Tanda ML, Piantanida E, Lai A. The role of somatostatin analogs in the management of Graves’ ophthalmopathy? J Endocrinol Invest 2003, 26 (Suppl to no. 8): 109–13.

    PubMed  CAS  Google Scholar 

  56. Kendall-Taylor P, Dickinson AJ, Vaidya B, et al. Double-blind placebo-controlled trial of octreotide LAR in thyroid-associated orbitopathy (TAO): clinical outcomes. Thyroid 2003, 15: 671 (abstract).

    Google Scholar 

  57. Prummel MF, Mourits MP, Berghout A, et al. Prednisone and cyclosporine in the treatment of severe Graves’ ophthalmopathy. N Engl J Med 1989, 321: 1353–9.

    Article  PubMed  CAS  Google Scholar 

  58. Smith JR, Rosenbaum JT. A role of methotrexate in the management of non-infectious orbital inflammatory disease. Br J Ophthalmol 2001, 85: 1220–4.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  59. Bouzas EA, Karadimas P, Mastorakos G, Koutras DA. Antioxidants agents in the treatment of Graves’ ophthalmopathy. Am J Ophthalmol 2000, 129: 618–22.

    Article  PubMed  CAS  Google Scholar 

  60. Balazs C, Kiss E, Vamos A, Molnar I, Farid NR. Beneficial effect of pentoxifylline on thyroid associated ophthalmopathy (TAO): a pilot study. J Clin Endocrinol Metab 1997, 82: 1999–2002.

    PubMed  CAS  Google Scholar 

  61. Bartalena L, Tanda ML, Medea A, Marcocci C, Pinchera A. Novel approaches to the management of Graves’ ophthalmopathy. Hormones 2002, 1: 76–90.

    Article  PubMed  Google Scholar 

  62. Bartalena L, Tanda ML, Piantanida E, Lai A, Pinchera A. Relationship between management of hyperthyroidism and course of the ophthalmopathy. J Endocrinol Invest 2004, 27: 288–94.

    Article  PubMed  CAS  Google Scholar 

  63. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves’ ophthalmopathy. N Engl J Med 1998, 338: 73–8.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Dipartimento di Medicina Clinica, Università dell’Insubria, Divisione di Endocrinologia, Ospedale di Circolo, Viale Borri, 57, 21100, Varese, Italy

    Luigi Bartalena

  2. Department of Endocrinology and Metabolism, University of Amsterdam, Amsterdam, The Netherlands

    W. M. Wiersinga

  3. Department of Endocrinology, University of Pisa, Pisa, Italy

    A. Pinchera

Authors
  1. Luigi Bartalena
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. W. M. Wiersinga
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Pinchera
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luigi Bartalena.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bartalena, L., Wiersinga, W.M. & Pinchera, A. Graves’ ophthalmopathy: State of the art and perspectives. J Endocrinol Invest 27, 295–301 (2004). https://doi.org/10.1007/BF03345280

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03345280

Key-words

Search

Navigation